Neurobiology of Suicide: Childhood Adversity, Neuroinflammation and Genomics

自杀的神经生物学：童年逆境、神经炎症和基因组学

• 批准号: 10408793
• 负责人: MARK D UNDERWOOD
• 金额: $ 27.53万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408793
• 关键词: Adult; Age; Anterior; Anxiety; Autopsy; Biological; Biological Assay; Biological Markers; Blood; Brain; Brain-Derived Neurotrophic Factor; Calcium Binding; Calcium ion; Cells; Cessation of life; Childhood; Cytokine Receptors; Cytoplasmic Granules; Data; Dendrites; Diagnosis; Dorsal; Environment; Epigenetic Process; Exposure to; Failure; Feeling suicidal; Fright; Funding; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; HDAC6 gene; Hippocampus (Brain); Histone Deacetylase; Human; ITGAM gene; Immunohistochemistry; Immunologic Monitoring; Impairment; Individual; Inflammasome; Inflammation; Inflammatory; Interleukins; Label; Length; Magnetic Resonance Imaging; Measures; Mental Depression; Messenger RNA; Microglia; Molecular Chaperones; Morphology; Neurobiology; Neuroglia; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Psychopathology; Quadruplet Multiple Birth; Reporting; Resistance; Rest; Risk; Risk Factors; Sampling; Serotonin Receptor 5-HT1A; Stress; Suicide; TNF gene; Thick; Thinness; Toxicology; Universities; adverse childhood events; biological adaptation to stress; childhood adversity; cingulate cortex; completed suicide; cytokine; delay sex; density; dentate gyrus; depressive symptoms; emotion regulation; high risk; immunocytochemistry; in vivo; indexing; inflammatory marker; memory process; neuroinflammation; neuron loss; neuropathology; psychologic; receptor binding; receptor expression; resilience; response; sex; suicidal behavior; suicidal risk; suicide attempter; trait

SUMMARY- PROJECT 1 Childhood adversity is associated with greater risk for adulthood depression (MDD), aggressive traits and suicide. The overall goal of Project 1 is to define a biological phenotype for suicide and assess the contribution of reported childhood (before age 16) adversity. In MDD suicides, we find a higher rate of childhood adverse events. The biological basis of this relationship is mostly unknown, but recent studies, including finds from our previous Conte Center of thinner prefrontal cortex (PFC) and smaller hippocampus (HC) volume and reduced BDNF, suggest glucocorticoid excess and impaired trophic effect is a consequence of stress and contributes to suicide risk. Stress and suicide are also associated with fewer cells and dendritic shrinkage in prefrontal cortex (PFC) and hippocampus (HC). The thinner PFC and smaller HC volume may constitute a biological risk factor for stress-related psychopathology. We hypothesize that this neurobiological phenotype may result from neuroinflammation, environment and epigenetic effects. In the new Conte Center, we aim to determine in the PFC and HC, whether inflammatory cytokines are increased, whether neurons, glia or both express those inflammatory markers, and whether the presence of those markers is associated with changes in neuron number or morphology in 5 groups (n=15 per group) of age- and sex-matched MDD suicides and nonpsychiatric controls with and without reported childhood adversity (before 15y) and 10 non suicide MDDs, all with psychological autopsy and brain toxicology. We propose to measure: 1) 62 markers of the inflammasome in the dorsal PFC (dPFC), ACC and HC; we will estimate total number of neurons and glia in HC and neuronal and glial density in the dPFC and ACC, with neurons and glia double-labeled with select cytokines identified from the inflammasome assay; 2) we will count the number of microglia in the HC (at anterior, mid- and posterior levels) and the density of microglia in dPFC and ACC using microglia specific markers; and 3) Determine the dendrite length and branching as indices of neuron morphology. Exploratory aims will: 1) separate the effect of MDD from that of suicide or adversity on neuron and glia expression of select inflammatory markers comparing the suicide and non-suicide MDD groups; 2) compare cytokines from brain and blood; TSPO level in postmortem brain and measured by PET; cortical thickness and HC volume in postmortem brain and measured in vivo by MRI. The proposed studies will provide evidence whether CA and suicide are associated with a neuroinflammatory response. !

摘要-项目1 儿童时期的逆境与成年后抑郁(MDD)、攻击性特征和 自杀。项目1的总体目标是定义自杀的生物学表型，并评估其贡献 儿童时期(16岁之前)所报告的逆境。在MDD自杀者中，我们发现儿童不良反应的比率更高 事件。这种关系的生物学基础大多是未知的，但最近的研究，包括从我们的发现 前额叶皮质(PFC)变薄和海马体(HC)体积变小的Conte中心 BDNF，提示糖皮质激素过多和营养作用受损是压力的结果，并有助于 自杀风险。压力和自杀也与前额叶皮质细胞减少和树突萎缩有关 (PFC)和海马区(HC)。较薄的PFC和较小的HC体积可能构成生物学风险因素 与压力相关的精神病态。我们推测这种神经生物学表型可能是由 神经炎症、环境和表观遗传效应。在新的Conte中心，我们的目标是在 PFC和HC，炎性细胞因子是否增加，无论是神经元、神经胶质细胞还是两者都表达这些 炎症标志物，以及这些标志物的存在是否与神经元的变化有关 5组(每组15例)年龄和性别匹配的MDD自杀者和 有或没有报告童年逆境的非精神病组(15岁之前)和10名非自杀的MDDS， 全部进行了心理尸检和脑毒学检查。我们建议测量：1)62个标记 背侧PFC(DPFC)、ACC和HC的炎症体；我们将估计神经元和胶质细胞总数 DPFC和ACC的HC、神经元和神经胶质细胞密度，神经元和神经胶质细胞用SELECT双标 炎性小体实验确定的细胞因子；2)我们将计算HC中小胶质细胞的数量(在 DPFC和ACC的小胶质细胞密度 标记；3)确定树突长度和分支作为神经元形态的指标。 探索性目标将：1)将MDD与自杀或逆境对神经元和神经胶质细胞的影响分开 自杀与非自杀MDD组部分炎症标志物表达的比较2)比较 脑组织和血液中的细胞因子；死后脑内的TSPO水平和PET测量；皮质厚度和 死后脑内HC体积及活体MRI测量。拟议的研究将提供证据 CA和自杀是否与神经炎性反应有关。 好了！